Glycogen Storage Disease Type V

Glycogen storage disease type V is a rare inherited condition that affects how muscles use stored energy, causing fatigue, pain, and cramps during physical activity. While symptoms usually begin in childhood or young adulthood, many people aren’t diagnosed until decades later due to the condition often being misdiagnosed or overlooked.

Table of contents

• What is glycogen storage disease type V?
• Other names for this condition
• Signs and symptoms
• What causes this condition
• How it is inherited
• How common is it
• How doctors diagnose the condition
• Treatment and management
• Possible complications
• Living with the condition

What is glycogen storage disease type V?

Glycogen storage disease type V is an inherited disorder that mainly affects the skeletal muscles, which are the muscles that allow you to move. The condition happens because the body cannot properly break down a complex sugar called glycogen (stored glucose) in muscle cells^[1].

Your body’s cells need a steady supply of fuel in the form of glucose, a simple sugar that is the main energy source. When you eat, excess glucose that is not needed right away is stored as glycogen in muscle and liver cells. When the body needs more energy, especially during physical activity, enzymes break down glycogen into glucose^[11].

In glycogen storage disease type V, an important enzyme called myophosphorylase (also called muscle glycogen phosphorylase) is missing or doesn’t work properly. This enzyme is found only in muscle cells, where it breaks down glycogen into a simpler sugar called glucose-1-phosphate. Additional steps then convert glucose-1-phosphate into glucose^[1].

Because muscle cells cannot produce enough energy from stored glycogen, muscles become easily fatigued. This lack of glycogen breakdown interferes with the function of muscle cells and leads to the major features of the condition^[1].

• Skeletal muscles
• Muscle cells

Other names for this condition

McArdle disease, McArdle syndrome, McArdle’s disease, Glycogen storage disease type 5, Glycogenosis 5, GSD type V, GSD V, Muscle glycogen phosphorylase deficiency, Muscle phosphorylase deficiency, Myophosphorylase deficiency, PYGM deficiency

The condition is also known as McArdle disease, named after Dr. Brian McArdle, a British physician who first reported it in 1951^[3].

Signs and symptoms

People with glycogen storage disease type V typically experience fatigue, muscle pain, and cramps during the first few minutes of exercise, a problem called exercise intolerance. Exercise such as weight lifting or jogging usually triggers these symptoms in affected individuals^[1].

The most common symptoms include:

• Getting tired easily from physical activity
• Muscle cramps
• Muscle weakness
• Muscle fatigue
• Muscle pain
• Muscle stiffness

All these symptoms are much more apparent soon after starting physical activity. The discomfort is generally alleviated with rest^[1]. People with this condition usually don’t have symptoms between episodes of physical activity^[6].

If individuals rest after brief exercise and wait for their pain to go away, they can usually resume exercising with little or no discomfort. This is a characteristic phenomenon known as the “second wind”^[1]. After a few minutes of rest, you may feel this “second wind” that lets you exercise again^[15].

You may be able to tolerate light-to-moderate exercise, like walking on level ground. But strenuous physical activity usually brings on symptoms quickly. Exercises that involve squeezing your muscles without any movement, like lifting heavy objects, squatting or standing on your tiptoes can cause muscle damage^[6].

When symptoms begin

In the classic form of the disease, the onset is usually noticed in childhood. The median age when symptoms begin is 3 years^[3]. The features of this condition typically begin in a person’s teens or twenties, but they can appear anytime from infancy to adulthood^[1]. However, diagnosis may not occur until a person is over 20 or 30 years old^[5].

Diagnostic delay and misdiagnosis

The condition is often not diagnosed until the third or fourth decade of life, frequently due to misdiagnosis and dismissal of symptoms. The median diagnostic delay is 29 years. Misdiagnosis is overwhelmingly common, with approximately 90% of patients being misdiagnosed, and approximately 62% receiving multiple misdiagnoses before a correct diagnosis^[3].

The prolonged diagnostic delay, misdiagnosis or multiple misdiagnoses, or being given inappropriate exercise advice severely impacts the quality of life, both physically and mentally^[3].

Variability of symptoms

The signs and symptoms can vary significantly in affected individuals. In most people with the condition, the muscle weakness worsens over time; however, in about one-third of affected individuals, the muscle weakness is stable. Some people experience mild symptoms such as poor stamina; others do not experience any symptoms^[1].

What causes this condition

Glycogen storage disease type V is a genetic condition. Changes (mutations) in the PYGM gene cause the condition. The PYGM gene provides instructions for your body to make an enzyme called myophosphorylase^[1].

PYGM gene mutations prevent myophosphorylase from breaking down glycogen effectively. As a result, muscle cells cannot produce enough energy, so muscles become easily fatigued. Reduced energy production in muscle cells leads to the major features of the condition^[1].

So far, researchers have found 179 variants that affect the PYGM gene^[6].

How it is inherited

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition^[1].

This means that to have the disorder, you must receive a copy of the nonworking gene from both parents. A person who receives a nonworking gene from only one parent usually does not develop this syndrome. A family history of glycogen storage disease type V increases the risk^[5].

How common is it

Glycogen storage disease type V is a rare disorder; however, its exact prevalence is unknown. In the Dallas-Fort Worth area of Texas, where the prevalence has been studied, the condition is estimated to affect 1 in 100,000 individuals^[1]. Researchers estimate that it affects 1 in 50,000 to 1 in 200,000 people in the United States^[6].

How doctors diagnose the condition

The diagnosis of glycogen storage disease type V is established in a person with suggestive findings through several methods. The preferred method is identification of changes in both copies of the PYGM gene through molecular genetic testing. If genetic test results are not diagnostic, diagnosis can be made by testing muscle myophosphorylase enzyme activity^[4].

The following tests may be performed:

• Genetic testing
• Muscle biopsy
• Electromyography (EMG)
• MRI
• Serum creatine kinase (blood test)
• Myoglobin in urine
• Lactic acid in blood
• Plasma ammonia
• Non-ischemic forearm test

These tests help doctors confirm the diagnosis and rule out other conditions^[5].

Treatment and management

Although no cure for glycogen storage disease type V is available, affected individuals benefit from proper management. There is no specific treatment, but the healthcare provider may suggest the following to stay active and healthy and prevent symptoms^[5]:

Physical activity recommendations

Affected individuals benefit from moderate-intensity aerobic training such as walking or brisk walking and bicycling to increase cardiorespiratory fitness and muscle oxidative capacity^[4].

The following guidelines help manage the condition:

• Be aware of your physical limitations
• Before exercising, warm up gently
• Avoid exercising too hard or too long
• Avoid intense isometric exercise and maximal aerobic exercise to prevent occurrence of cramps

Dietary approaches

Pre-exercise ingestion of sports drinks containing simple carbohydrates improves exercise tolerance and may protect against exercise-induced muscle breakdown^[4].

Healthcare providers may recommend:

• Eating enough protein
• Eating some sugar before exercising, which may help prevent muscle symptoms

Medical considerations

If you need to have surgery, ask your provider if it’s safe for you to have general anesthesia^[5].

Pharmacological treatments

A systematic review of randomized controlled trials found no benefit with several tested medications including D-ribose, glucagon, verapamil, vitamin B6, branched chain amino acids, dantrolene sodium, and high-dose creatine. Minimal subjective benefit was found with low doses of creatine^[7].

Possible complications

Prolonged or intense exercise can cause muscle damage in people with glycogen storage disease type V. About half of people with the condition experience breakdown of muscle tissue, called rhabdomyolysis^[1].

In severe episodes, the destruction of muscle tissue releases a protein called myoglobin, which is filtered through the kidneys and released in the urine. This is called myoglobinuria. Myoglobin causes the urine to be red or brown, sometimes described as burgundy-colored urine^[1].

This protein can also damage the kidneys. It is estimated that half of those individuals with the condition who have myoglobinuria will develop life-threatening kidney failure^[1]. This is a life-threatening condition that can cause acute (sudden and severe) kidney failure and dangerous high potassium levels^[6].

It’s important to be mindful of how much and how hard you exercise to try to prevent rhabdomyolysis. Get immediate medical help if you develop symptoms like muscle swelling and dark urine that’s brown, red or tea-colored^[6].

Contact your healthcare provider if you have repeated episodes of sore or cramped muscles after exercise, especially if you also have burgundy or pink urine^[5].

Living with the condition

People with glycogen storage disease type V can live a normal life by managing their diet and physical activity^[5]. Despite the lack of a cure, proper management can improve the quality of life and reduce symptoms for many patients^[2].

When the family-specific PYGM gene changes are known, early detection of the condition in relatives at risk ensures proper management to prevent muscle injury leading to rhabdomyolysis and to improve long-term outcome, particularly by development of a healthy lifestyle, such as regular exercise like brisk walking, in childhood^[4].

Consider genetic counseling if you have a family history of glycogen storage disease type V^[5].

Glycogen Storage Disease Type V
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